Nucleotide Metabolism

George L. Mendz

doi:10.1128/9781555818005.ch13

Chapter 13 : Nucleotide Metabolism

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: School of Biochemistry and Molecular Genetics, The University of New South Wales, Sydney NSW 2052, Australia

Content Type: Monograph

Publication Year: 2001

Category: Bacterial Pathogenesis

Book DOI: 10.1128/9781555818005

Chapter DOI: 10.1128/9781555818005.ch13

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

Nucleotide Metabolism, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555818005/9781555812133_Chap13-1.gif /docserver/preview/fulltext/10.1128/9781555818005/9781555812133_Chap13-2.gif

Abstract:

A complete understanding of the nucleotide metabolism of Helicobacter pylori is of fundamental interest to microbiology and also will help in the development of new anti-H. pylori therapies. Pyrimidines and purines are essential for the synthesis of nucleoside triphosphates, which are precursors of nucleic acids. Nucleoside polyphosphates are formed by successive phosphorylations of their monophosphate counterparts. Pyrimidine ribonucleotide synthesis includes De Novo pyrimidine nucleotide synthesis, carbamoyl phosphate synthetase and aspartate carbamoyl transferase. The de novo synthesis of purine nucleotides is carried out by pathways that are similar throughout the biological world, but many organisms obtain their nucleotide needs utilizing preformed purine compounds through salvage pathways that take up available purine nucleobases and nucleosides. The thymidine triphosphate (dTTP) salvage pathway described in Escherichia coli requires the presence of uridine phosphorylase or thymidine phosphorylase, and thymidine kinase, encoded by udp, deoA, and tdk genes, respectively. There are only a few studies on the nucleotide metabolism of H. pylori, but together with the information derived from analyses of the genome of the bacterium, they have provided a wealth of information about the pathways of biosynthesis and degradation of pyrimidine and purine nucleotides, and showed that nucleotide biosynthetic enzymes are potential targets for antimicrobials designed against the organism.

Citation: Mendz G. 2001. Nucleotide Metabolism, p 147-158. In Mobley H, Mendz G, Hazell S (ed), Helicobacter pylori. ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch13

Key Concept Ranking

Nuclear Magnetic Resonance Spectroscopy: 0.44805047
Nucleoside Diphosphates: 0.41769868

0.44805047

Highlighted Text: Show | Hide

Full text loading...

Figures

Nucleotide Metabolism

[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555818005.chap13-1,webId=/content/author/10.1128/9781555818005.chap13-1,properties={foaf_givenname=George L., foaf_name=George L. Mendz, foaf_surname=Mendz, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555818005.chap13-aff1]]}]]

Citation: Mendz G. 2001. Nucleotide Metabolism, p 147-158. In Mobley H, Mendz G, Hazell S (ed), Helicobacter pylori. ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch13

/content/10.1128/9781555818005.chap13.fig13-1

Figure 1

De novo pyrimidine biosynthesis pathway. The enzymes encoded by the pyr genes are pyrA, carbamoyl phosphate synthase; pyrB, aspartate carbamoyl transferase; pyrC, dihydroorotase; pyrD, dihydroorotase dehydrogenase; pyrE, orotate phosphoribosyltransferase; pyrF, orotidylate decarboxylase; pyrH, UMP kinase; ndk, nucleoside diphosphokinase; and pyrG, CTP synthetase. The nucleotides are OMP, orotidine monophosphate; UMP, uridine monophosphate; UDP, uridine diphosphate; UTP, uridine triphosphate; and CTP, cytosine triphosphate.

10.1128/9781555818005/fig13-1_thmb.gif

10.1128/9781555818005/fig13-1.gif

Figure 1

Citation: Mendz G. 2001. Nucleotide Metabolism, p 147-158. In Mobley H, Mendz G, Hazell S (ed), Helicobacter pylori. ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch13

/content/10.1128/9781555818005.chap13.fig13-2

Figure 2

De novo purine biosynthesis pathway. The enzymes encoded by the pur genes are purF, glutamine:PRPP-amido-transferase; purD, phosphoribosylglycinamide (GAR) synthetase; purN, GAR transformylase N; purT, GAR transformylase T; purL, phosphoribosyl-N-formylglycinamide synthetase; purM, phosphoribosyl-aminoimidazole synthetase; purK, phosphoribosyl-carboxyaminoimidazole synthetase; purE, phosphoribosyl-carboxyaminoimidazole mutase; purC, phosphoribosyl-N-succino-carboxamide-aminoimidazole; purB, adenylosuccinate lyase; purH, phosphoribosyl-carboxamide-aminoimidazole transformylase; and purH, inosinic acid cyclohydrolase. The compounds are Gln, glutamine; PPi, pyrophosphate; Glu, glutamate; ATP, adenosine triphosphate; ADP, adenosine diphosphate; Pi, phosphate; N-Formyl-THF, N 10-formyl-tetrahydrofolate; THF, tetrahydrofolate; CO2, carbon dioxide; Asp, aspartate; and H2O, water.

10.1128/9781555818005/fig13-2_thmb.gif

10.1128/9781555818005/fig13-2.gif

Figure 2

Citation: Mendz G. 2001. Nucleotide Metabolism, p 147-158. In Mobley H, Mendz G, Hazell S (ed), Helicobacter pylori. ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch13

/content/10.1128/9781555818005.chap13.fig13-3

Figure 3

De novo synthesis of ATP and GTP. The enzymes encoded by the different genes are guaB, IMP dehydrogenase; guaA, GMP synthase; gmk, GMP kinase; ndk, nucleoside diphosphokinase; purA, adenylosuccinate synthetase; purB, adenylosuccinate lyase; and adk, adenylate kinase. The nucleotides are IMP, inosine monophosphate; XMP, xanthosine monophosphate; GMP, guanosine monophosphate; GDP, guanosine diphosphate; GTP, guanosine triphosphate; AMP, adenosine monophosphate; ADP, adenosine diphosphate; and ATP, adenosine triphosphate. The asterisk denotes a gene not identified in the genome or whose corresponding enzyme activity has not been observed.

10.1128/9781555818005/fig13-3_thmb.gif

10.1128/9781555818005/fig13-3.gif

Figure 3

Citation: Mendz G. 2001. Nucleotide Metabolism, p 147-158. In Mobley H, Mendz G, Hazell S (ed), Helicobacter pylori. ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch13

/content/10.1128/9781555818005.chap13.fig13-4

Figure 4

Salvage and interconversion of purines. The enzymes encoded by the different genes are deoD, purine nucleoside phosphorylase; apt, adenine phosphoribosyl transferase; purB, adenylosuccinate lyase; purA, adenylosuccinate synthetase; guaC, GMP reductase; gpt, guanine phosphoribosyl transferase; guaB, IMP dehydrogenase; and guaA, GMP synthase. The purine bases are A, adenine; G, guanine; and Hx, hypoxanthine. Ribonucleosides and deoxyribonucleosides are identified by R and dR, respectively. Nucleotide monophosphates are identified by MP with XMP as xanthosine monophosphate. Nucleotide triphosphates are identified by TP. The asterisk represents a gene whose enzyme activity has not been detected.

10.1128/9781555818005/fig13-4_thmb.gif

10.1128/9781555818005/fig13-4.gif

Figure 4

Citation: Mendz G. 2001. Nucleotide Metabolism, p 147-158. In Mobley H, Mendz G, Hazell S (ed), Helicobacter pylori. ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch13

/content/10.1128/9781555818005.chap13.fig13-5

Figure 5

Biosynthesis of deoxyribonucleotides. The enzymes encoded by the different genes are nrd, ribonucleoside diphosphate reductase; ndk, nucleoside diphosphokinase; dcd, dCTP deaminase; dut, deoxyuridine triphosphatase; thyA, thymidylate synthase; tmk, thymidylate kinase; and ndk, nucleoside diphosphokinase. In the nucleotides N can be A, C, and U; dNDP, deoxynucleoside diphosphate; dATP, deoxyadenosine triphosphate; dCTP, deoxycytidine triphosphate; dUTP, deoxyuridine tiphosphate; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate; dTDP, deoxythymidine diphosphate; and dTTP, deoxythymidine triphosphate. The asterisk denotes a gene that has not been identified in the genome.

10.1128/9781555818005/fig13-5_thmb.gif

10.1128/9781555818005/fig13-5.gif

Figure 5

Citation: Mendz G. 2001. Nucleotide Metabolism, p 147-158. In Mobley H, Mendz G, Hazell S (ed), Helicobacter pylori. ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch13

References

/content/book/10.1128/9781555818005.chap13

1. Adair, L. B.,, and M. E. Jones. 1972. Purification and characteristics of aspartate transcarbamylase from Pseudomonas fluoresce™. J. Biol. Chem. 247: 2308– 2315.

2. Ahonkhai, I.,, M. Kamekura,, and D. J. Kushner. 1989. Effects of salts on the aspartate transcarbamylase of a halophilic bacterium , Vibrio costicola. Biochem. Cell Biol. 67: 666– 669.

3. Aim, R. A.,, L. S. Ling,, D. T. Moir,, B. L. King,, E. D. Brown,, P. C. Doig,, D. R. Smith,, B. Noonan,, B. C. Guild,, B. L. dejonge,, G. Carmel,, P. J. Tummino,, A. Caruso,, M. Uria-Nickelsen,, D. M. Mills,, C. Ives,, R. Gibson,, D. Merberg,, S. D. Mills,, Q. Jiang,, D. E. Taylor,, G. F. Vovis,, and T. J. Trust. 1999. Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature 397: 176– 180.

4. Bergh, S. T.,, and D. R. Evans. 1993. Subunit structure of class A aspartate transcarbamylase from Pseudomonas fluorescens. Proc. Natl. Acad. Sci. USA 90: 9818– 9822.

5. Bethell, M. R.,, and M. E. Jones. 1969. Molecular size and feedback-regulation of bacterial aspartate transcarbamylase. Arch. Biochem. Biophys. 134: 352– 365.

6. Burns, B. P.,, S. L. Hazell,, and G. L. Mendz. 1997. In situ properties of aspartate carbamoyltransferase activity in Helicobacter pylori. Arch. Biochem. Biophys. 347: 119– 125.

7. Burns, B. P.,, S. L. Hazell,, and G. L. Mendz. 1998. A novel mechanism for resistance to the antimetabolite N-phosphonoacetyl-L-aspartate by Helicobacter pylori. J. Bacteriol. 180: 5574– 5579.

8. Burns, B. P.,, S. L. Hazell,, G. L. Mendz,, T. Kolesnikow,, D. Tillett,, and B. A. Neilan. 2000. The Helicobacter pylori pyrB gene encoding aspartate carbamoyltransferase is essential for survival. Arch. Biochem. Biophys. 380: 78– 84.

9. Chang, T.-Y.,, and M. E. Jones. 1974. Aspartate transcarbamylase from Streptococcus faecalis. Purification, properties, and nature of an allosteric activator site. Biochemistry 13: 629– 638.

10. Chu, C.,, and T. P. West. 1990. Pyrimidine biosynthetic pathway of Pseudomonas fluorescens. J. Gen. Microbiol. 136: 875– 880.

11. Copeland, R. A.,, J. Marcinkeviciene,, T. S. Haque,, L. M. Kopcho,, W. Jiang,, K. Wang,, L. D. Ecret,, C. Sizemore,, K. A. Amsler,, L. Foster,, S. Tadesse,, A. P. Combs,, A. M. Stern,, G. L. Trainor,, A. Slee,, M. J. Rogers,, and F. Hobbs. 2000. Helicobacter pylori-selective antibacterials based on inhibition of pyrimidine biosynthesis. J. Biol. Chem. 275: 33373– 33378.

12. Grem, J. L.,, S. A. King,, P. J. O'Dwyer,, and B. Leyland-Jones. 1988. Biochemistry and clinical activity of N-(phosphona-cetyl)-L-aspartate: a review. Cancer Res. 48: 4441– 4454.

13. Guy, H. I.,, and D. R. Evans. 1994. Cloning and expression of the mammalian multifunctional protein CAD in Escherichia coli. Characterization of the recombinant protein and a deletion mutant lacking the major interdomain linker. J. Biol. Chem. 269: 23808– 23816.

14. Jyssum, S.,, and K. Jyssum. 1979. Metabolism of pyrimidine bases and nucleosides in Neisseria meningiditis. J. Bacteriol. 138: 320– 323.

15. Kaneko, T.,, A. Tanako,, S. Sato,, H. Kotani,, T. Sazuka,, N. Miyajima,, M. Sugiura,, and S. Tabata. 1997. Sequence analysis of the genome of the unicellular cyanobacterium Synechocystis sp. strain PCC 6803.1. Sequence features in 1 Mb region from map position 64% to 92% of the genome. DNA Res. 2: 153– 166.

16. Kenny, M. J.,, D. McPhail,, and M. Shepherdson. 1996. A reappraisal of the diversity and class distribution of aspartate transcarbamylases in gram-negative bacteria. Microbiology 142: 1873– 1879.

17. Mendz, G. L.,, B. M. Jimenez,, S. L. Hazell,, A. M. Gero,, and W. J. O'Sullivan. 1994. De novo synthesis of pyrimidine nucleotides by Helicobacter pylori. J. Appl. Bacteriol. 77: 1– 8.

18. Mendz, G. L.,, B. M. Jimenez,, S. L. Hazell,, A. M. Gero,, and W.J. O'Sullivan. 1994. Salvage synthesis of purine nucleotides by Helicobacter pylori. J. Appl. Bacteriol. 77: 674– 681.

19. Mendz, G. L.,, A. J. Shepley,, and S. L. Hazell. 1996. Survival of Helicobacter pylori by de novo synthesis of pyrimidine nucleotides. Gut Suppl. 39: A73.

20. Mendz, G. L.,, A. J. Shepley,, S. L. Hazell,, and M. A. Smith. 1997. Purine metabolism and the microaeropohily of Helicobacter pylori. Arch. Microbiol. 168: 448– 456.

21. Neuhard, J.,, and R. A. Kelln,. 1996. Biosynthesis and conversion of pyrimidines, p. 580– 599. In F. C. Neidhart (ed.), Escherichia coli and Salmonella: Cellular and Molecular Biology, 2nd ed. American Society for Microbiology, Washington, D.C..

22. Neumann, J.,, and M. E. Jones. 1964. End-product inhibition of aspartate transcarbamylase in various species. Arch. Biochem. Biophys. 104: 438– 447.

23. Nygaard, P., 1993. Purine and pyrimide salvage pathways, p. 359– 378. In A. L. Sonenshein (ed.), Bacillus subtilis and Other Gram-Positive Bacteria: Biochemistry, Physiology and Molecular Genetics. American Society for Microbiology, Washington, D.C..

24. O'Donovan, G. A.,, and J. Neuhard. ( 1970 ) Pyrimidine metabolism in microorganisms. Bacteriol. Rev. 34: 278– 343.

25. Pragobpol, S.,, A. M. Gero,, C. S. Lee,, and W. J. O'Sullivan. 1984. Orotate phosphorybosyltransferase and orotidylate decarboxylase from Crithidia luciliae. Subcellular location of the enzymes and evidence for substrate channeling. Arch. Biochem. Biophys. 230: 285– 293.

26. Purcarea, C.,, G. Erauso,, D. Prieur,, and G. Herve. 1994. Aspartate transcarbamylase from the deep-sea hyperthermophile archeon Pyrococcus abyssi: genetic organisation, structure, and expression in Escherichia coli. Microbiology 140: 1967– 1975.

27. Quinn, C. L.,, B. T. Stephenson,, and R. L. Switzer. 1991. Functional organisation and nucleotide sequence of the Bacillus subtilis pyrimidine biosynthetic operon. J. Biol. Chem. 266: 9113– 9127.

28. Reynolds, D. J.,, and C.W. Penn. 1994. Characteristics of Helicobacter pylori growth in a defined medium and determination of its amino acid requirements. Microbiology 140: 2649– 2656.

29. Roland, K. L.,, F. E. Powell,, and C. L. Turnbough. 1985. Role of translation and attenuation in the control of pyrBI expression in Escherichia coli. J. Bacteriol. 163: 991– 999.

30. Roth, B., 1983. Selective inhibitors of bacterial dihydrofolate reductase: structure-activity relationships, p. 107– 127. In G. H. Hitchings (ed.), Inhibition of Folate Metabolism in Chemotherapy. Springer-Verlag, Berlin, Germany.

31. Shepley, A. J.,, G. L. Mendz,, and S. L. Hazell. 1995. The essential role of de novo pyrimidine nucleotide synthesis in Helicobacter pylori, abstr. P-58. In Proc. 7th PAOBMB Congress. Australian Society for Biochemistry and Molecular Biology, Sydney, Australia.

32. Swyryd, E. A.,, S. S. Seaver,, and G. R. Stark. 1974. N-(phosphonacetyl)-L-aspartate, a potent transition state analog inhibitor of aspartate transcarbamylase, blocks proliferation of mammalian cells in culture. J. Biol. Chem. 249: 6945– 6950.

33. Tomb, J. F.,, O. White,, A. R. Kerlavage,, R. A. Clayton,, G. G. Sutton,, R. D. Fleishmann,, K. A. Ketchum,, H. P. Kienk,, S. Gill,, B. A. Dougherty,, K. Nelson,, J. Quackenbuch,, L. Zhou,, E. F. Kirkness,, S. Peterson,, B. Loftus,, D. Richardson,, R. Dodson,, H. G. Khalk,, A. Glodek,, K. McKenney,, L. M. Fitzgerald,, M. Lee,, M. D. Adams,, E. K. Hickey,, D. E. Berg,, I. D. Gocayne,, C. Fujii,, C. Bowman,, L. Watthey,, E. Wallin,, W. S. Hayes,, M. Borodovsky,, P. D. Karp,, H. O. Smith,, C. M. Fraser,, and J. C. Venter. 1997. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388: 539– 547.

34. Traut, T. W.,, and M. E. Jones. 1977. Inhibitors of orotate phosphoribosyl-transferase and orotidine-5'-decarboxylase from mouse Ehrlich ascites cells: a procedure for analyzing the inhibition of a multi-enzyme complex. Biochem. Pharmacol. 26: 2291– 2296.

35. Turner, R. J.,, Y. Lu,, and R. L. Switzer. 1994. Regulation of the Bacillus subtilis pyrimidine biosynthetic (pyr) gene cluster by an autogenous transcriptional attenuation mechanism. J. Bacteriol. 176: 3708– 3722.

36. Umezu, K.,, T. Amaya,, A. Yoshimoto,, and K. Tomita. 1971. Purification and properties of orotidine-5'-phosphate pyrophosphorylase and orotidine-5'-phosphate decarboxylase from baker's yeast . J. Biochem. (Tokyo) 70: 249– 262.

37. Wheeler, P. R. 1990. Recent research into the physiology of Mycobacterium leprae. Adv. Microb. Physiol. 31: 71– 124.

38. Wild, J. R.,, and W. L. Belser. 1977. Pyrimidine biosynthesis in Serratia marcescens: a possible role for nonsequential enzyme interactions in mimicking coordinate gene expression. Biochem. Genet. 15: 157– 172.

39. Wild, J. R.,, and W. L. Belser. 1977. Pyrimidine biosynthesis in Serratia marcescens: polypeptide interactions of three nonsequential enzymes. Biocbem. Genet. 15: 173– 180.

40. Zalkin, H.,, and P. Nygaard,. 1996. Biosynthesis of purine nucleotides, p. 561– 579. In F. C. Neidhart (ed.), Escherichia coli and Salmonella: Cellular and Molecular Biology, 2nd ed. American Society for Microbiology, Washington, D.C.. 31: 117– 118.